ABSTRACT ? Project 2 ? Influence of controlled diets on gut microbiome, metabolome and cognitive function There is evidence from epidemiological studies that dietary interventions influence age-associated cognitive decline as well as the development of Alzheimer?s disease (AD). This Project is designed to test the effects of different dietary interventions on gut microbiome composition and function, blood and fecal metabolomes, and cognitive decline and investigate the mechanism(s) and interrelations between molecular layers that relate to these effects. One possible mechanism mediating beneficial effects of diet on brain health may be via changes to gut microbiome composition. Indeed, it is well-established that diet impacts the gut microbiota community structure and function which in turn can have a wide variety of biological effects on host metabolism and the immune system. Recent studies suggest that gut microbiota may also affect brain function. The Alzheimer?s Disease Metabolomics Consortium (ADMC) and the Accelerated Medicine Partnership for Alzheimer?s disease (AMP-AD) have identified metabolic signatures that correlate with markers of AD and AD progression. We now have the unprecedented opportunity to expand on this work by examining the effect of dietary interventions on microbiome composition and function, as well as metabolic signatures in order to understand how these effects relate to cognitive decline and other AD-relevant outcomes. Specifically, this Project will utilize samples collected in three different clinical trials: MIND, U.S. POINTER, and BEAT-AD. Two of the studies will evaluate effects of the MIND diet, which is a hybrid of the Mediterranean and DASH (dietary approaches to stop hypertension) diets with modifications based on scientific evidence of effects on brain health (MIND, U.S. POINTER). The third trial (BEAT-AD) will test the effects of the Modified Mediterranean-Ketogenic Diet (MMKD). This Project will profile blood and fecal samples collected from more than 1,700 participants enrolled in the three different clinical trials using state-of-the art metagenomics and metabolomics technologies to define the effects of each dietary intervention on gut microbiome, metabolome and relate these outcomes to pre-defined AD metabolic signatures, brain structure and function, and behavior. These studies are expected to increase our understanding of AD pathogenesis and potential treatments, by highlighting the crucial role of diet and the microbiota-brain axis, supporting our endeavors to identify potential therapeutic targets.